Cytokines include interferons, interleukins, growth factors and other molecules involved in signalling between cells. They play important stimulatory or inhibitory roles in a wide range of normal and pathologic processes such as growth regulation, inflammation, repair, viral and malignant diseases. The long-term objective of this research proposal is to define the role in tumor formation, spread or treatment of a new human cytokine, which we call hIRH, in selected gastrointestinal tissues and malignancies. Subtractive hybridization techniques to compare differences in gene expression at the cDNA level have been used to isolate potentially important genes in malignancy, such as the metastasis suppressor gene nm23. For a more rapid determination of differential gene expression at the cDNA level the technique of differential display has detected new genes, or suggested new roles for known genes in selected malignancies, e.g. maspin and integrins in breast cancer, PTI-1 in prostate cancer. We have isolated, by differential display, a range of new and known genes which we have determined to be differentially expressed in several gastrointestinal malignancies. This proposal focuses on one such gene, hIRH, isolated from differential displays of hepatocellular carcinoma and adjacent non-neoplastic liver, and continues studies to define its potential role in selected gastrointestinal malignancies. The specific aims are to define 1) the genetic structure, and 2) the possible functional role in hepatocellular carcinoma and other tissues, of hIRH which we have determined to be almost uniformly lost from hepatocellular carcinomas, in comparison with the adjacent non-neoplastic livers. Similar cytokines are important either directly, or indirectly via the induction of an inflammatory response, in the inhibition of tumor growth. We plan to assess the activity of hIRH on leukocyte chemotaxis and in growth inhibition, both highly significant processes in tumor biology.